1. Field of the Invention
The present invention relates to a process for the preparation of 2,2-difluoroethylamine by reaction of prop-2-en-1-amine with 2,2-difluoro-1-haloethane.
2. Description of Related Art
2,2-Difluoroethylamine is an important intermediate in the preparation of active substances. Various methods for the preparation of 2,2-difluoroethylamine are known.
Donetti et al. (J. Med. Chem., 1989, 32, 957-961) describe the synthesis of 2,2-difluoroethylamine hydrochloride starting from 2,2-difluoroacetamide. In this connection, the desired amine is prepared with a diborane solution in tetrahydrofuran (THF). The yield is 48%.
Kluger et al. (JACS, 1982, 104, 10, 2891-2897) describe the synthesis of 2,2-difluoroethylamine starting from the amide with sodium borohydride and boron trifluoride etherate. The yield is 60%. Vyazkov, V. A. et al. (Vyazkov, V. A., Gontar, A. F., Grinevskaya, V. K., Igoumnova, E. V. and Igoumnov, S. M., A. N.) Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow, Russia Fluorine Notes (2009), 65) likewise describe the reduction with sodium borohydride in a yield of 50-65%.
In addition, Kollonitsch (U.S. Pat. No. 4,030,994) describes a synthesis of 2,2-difluoroethylamine, namely the reaction of ethylamine with fluoroxytrifluoromethane in hydrogen fluoride under UV radiation.
In a paper with a title “Über einige fluorhaltige Alkylamine” [On some fluorine-comprising alkylamines] (Chem. Zentralblatt, Volume 75, 1904, pages 944-945), Swarts describes the preparation of 2,2-difluoroethylamine and of tetrafluoroethylamine, with subsequent separation of the two products by fractional distillation or as hydrochloride or oxalate salts, after prior conversion of the products obtained. Swarts uses 1-bromo-2,2-difluoroethane as starting compound and heats this over a relatively long period of time, namely 3 days, in the reactor tube with 2 mol of alcoholic ammonia at relatively high temperatures, namely 125-145° C. The starting compound is completely converted into the compounds difluoroethylamine and tetrafluoroethylamine.
The preparation of 2,2-difluoroethylamine is also described by Dickey et al. (Industrial and Engineering Chemistry, 1956, No. 2, 209-213). 2,2-Difluoro-1-chloroethane is there reacted with 28% ammonium hydroxide, i.e. 28% aqueous ammonia solution, in an autoclave (rocking autoclave). The reaction mixture is heated at temperatures of 135° C. to 140° C. for 31 hours. After the reaction has ended, the reaction mixture is filtered and the amine is distilled off from the reaction mixture. However, since a lot of ammonia and some water are still found in the distillate, the amine is dried over sodium hydroxide and again distilled. The amine was thus obtained in a yield of 65%.
This process is disadvantageous as it requires, just as the process according to Swarts, a very long reaction time of 31 hours and the yield of 65% is rather low. At the same time, the reaction mixture is highly corrosive since the aqueous ammonia, in combination with the chloride and fluoride ions present in the reaction mixture, attacks metallic materials at the high temperatures used in the process.
All these known processes are disadvantageous, in particular because they cannot be carried out on an economically useful commercial (industrial) scale. The low yield and the use of expensive and dangerous chemicals, such as, e.g., sodium borohydride/BF3 or diborane, prevent the processes according to Donetti et al. and Kluger et al. from being suitable for the commercial-scale preparation of 2,2-difluoroethylamine. The process according to Kollonitsch et al. uses dangerous chemicals and pure 2,2-difluoroethylamine is not obtained. The process according to Dickey et al. and the process according to Swarts are likewise unsuitable or uneconomic for commercial-scale use as they require very long reaction times and are at the same time non-selective, so that the yields of the processes are unsatisfactory.
Furthermore, the use of ammonia at high temperatures is problematic, since special pressure-resistant equipment is required, which is demanding and expensive from a safety viewpoint.
Starting from the known processes for the preparation of 2,2-difluoroethylamine, the question now arises of how 2,2-difluoroethylamine can be prepared in a simple and inexpensive way. The term “inexpensive processes” is understood to mean those processes which can be carried out without large financial expenditure because the starting materials, for example, are not dangerous, no other technical problems emerge, for example because the reaction mixture acts corrosively, and/or the desired 2,2-difluoroethylamine is obtained in a satisfactorily high yield and purity, because, for instance, the reaction takes place largely selectively.